The Nocebo Effect


The nocebo effect is the opposite of the placebo effect. In other words, it refers to negative side effects which appear when the patient has negative expectations from a treatment, even if the administered “treatment” is inert.

One consequence of the nocebo effect is that warning patients about the side effects of a certain medication can lead them to experience such effects, and in clinical trials this occurs regardless of whether they are receiving the active drug or not.

A meta-analysis including 1.271 randomized clinical trials with approximately 250.000 participants, found that approximately half of all people who received the inactive drug still reported side effects.

Understanding the neurobiology of the nocebo effect is important, as it could guide therapeutic strategies for reducing this unpleasant effect in patients. But studying the nocebo effect in humans poses significant ethical problems, as inducing anxiety in patients might further aggravate their health issues.

Similar to the placebo effect, however, nocebo can be studied in relation to pain (even here, only for healthy volunteers). In these studies, no treatment is administered, but verbal suggestions are used.

Participants receive a mildly painful stimulus, such as a cold ice cube applied on the hand. Prior to the stimulus, the experimenter describes to the participant the level of pain they should be expecting. Studies have shown that participants who are expecting a high level of pain will perceive the stimulus as more painful compared to those who are expecting a less painful stimulus, even though the true intensity of the stimulus is the same.

Additionally, they show increased activity both in pain-related areas, such as the insula or even the primary somatosensory cortex, as well as in areas responsible for cognitive control, such as the prefrontal cortex or the anterior cingulate cortex. In contrast, expectations of low pain have been shown to actually decrease activation in pain-related areas.

Taken together, both nocebo and its counterpart, placebo, underscore how important expectations and cognitive control are when it comes to treatment efficacy.

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Benedetti, F., Lanotte, M., Lopiano, L., & Colloca, L. (2007). When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience, 147(2), 260-271.

Howick, J., Webster, R., Kirby, N., & Hood, K. (2018). Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials. Trials, 19(1), 1-8.

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